1. Field of the Invention
The present invention relates to novel methods for producing aminopyrimidine compounds which are useful as intermediates for producing various compounds having pharmacological activity. The present invention also relates to certain novel aminopyrimidine compounds.
2. Discussion of the Background
Aminopyrimidine compounds represented by formula (3):
wherein R1 is an alkyl group optionally having substituents or an aralkyl group optionally having substituents; and R2 is an alkyl group optionally having substituents, an aryl group optionally having substituents, an aralkyl group optionally having substituents, or a group represented by the formula (a), the formula (b), or the formula (c):
wherein R3 is an alkyl group optionally having substituents, an aryl group optionally having substituents, or an aralkyl group optionally having substituents; and R4 is a hydrogen atom, an alkyl group optionally having substituents, an aryl group optionally having substituents, or an aralkyl group optionally having substituents,
are useful as intermediates for various compounds having pharmacological activity, such as anticancer agents, NK1 antagonists, elastase inhibitors and the like (see, e.g., U.S. Pat. No. 6,380,206 and WO02/42280, which are incorporated herein by reference in their entireties).
It has long been known to introduce an amino group into the 5-position of pyrimidine by introducing a nitro group into uracil and then reducing the same (see, J. Chem. Soc., pp. 1565-1570 (1951)).

However, since nitro compounds are generally feared due to the risk of explosion, they are not necessarily suitable for an industrial production method. In addition, since uracil derivatives have a carbonyl group at both the 2-position and the 4-position, regioselective introduction of a substituent into the 2-position or the 4-position is known to be difficult (see, J. Chem. Soc. Perk. Trans. 1, (7), pp. 919-922 (1992), EP 647639A, and Tetrahedron, vol. 58 (11), pp. 2147-2153 (2002)).
As a method of producing an aminopyrimidine compound using a compound other than uracil as a starting material, for example, a method shown in the following reaction scheme has been reported (see, J. Chem. Soc., Perk. Trans. 1, (7), pp. 1659-1664 (1992)):
wherein Ph is a phenyl group, Et is an ethyl group, and Bz is a benzoyl group.
According to this method, however, the amino-protecting group at the 5-position is a benzoyl group, which requires severe conditions for deprotection, such as use of a strong base or a strong acid and refluxing for a long time, which in turn limits the types of groups that can be introduced into the compound. Thus, this compound is not necessarily satisfactory for use as an intermediate compound for a pharmaceutical product, and a production method capable of introducing a protecting group that can be removed under milder conditions has been desired. In contrast, when an amino group at the 5-position of an aminopyrimidine compound is protected with an aliphatic acyl group, deprotection can be performed under comparatively mild conditions. However, a compound in which 2-phenyl-4-ethoxymethylene-azlactone, which is a starting material to be used for this reaction, contains an aliphatic group at the 2-position can be obtained only in a comparatively low yield (see, WO03/106434).
A different production method comprises reacting glycine ethyl ester with ethyl formate and sodium methoxide to give an ethyl-α-formyl-formyl glycinate sodium salt, and reacting this salt with an acid addition salt of amidine in methanol to give formylaminopyrimidine (see, Collect. Czech Chem. Comm., vol. 51 (1), pp. 215-233 (1986)). As regards this production method, however, there is no report on an aminopyrimidine compound, in which an amino group at the 5-position is protected with an aliphatic acyl group.
Thus, there remains a need for an improved method for producing aminopyrimidine compounds which are useful as intermediates for producing various compounds having pharmacological activity. There also remains a need for novel aminopyridine compounds which are useful as intermediates for producing various compounds having pharmacological activity.